The EGFR (Epidermal growth factor receptor) is a tyrosine kinase receptor of the ER (ErbB) family. The EGFR is known to be playing important roles in cell differentiation, cell proliferation, and maintenance of the state of cells in normal tissue, and also, in carcinoma tissue, to be heavily involved in growth, invasion, and metastasis. Signal transduction downstream of the EGFR is carried out by KRAS.
Signal transduction downstream of RAS is mainly carried out via the RAF-MEK-ERK cascade. It is also carried out via the SEK-JNK cascade, in which SEK and JNK are members of the broad MAPK family, the PI3K-AKT cascade that is deeply involved in apoptosis, the DAG-PKC cascade, and the JAK-STAT cascade, for example. A signal from a receptor like EGFR is transduced via such a cascade into the nucleus, where the signal activates various transcriptional factors and induces proliferation, survival, invasion, and anti-apoptotic activity of the cells.
The KRAS gene is known as a colorectal cancer proto-oncogene. KRAS-gene mutation is found in about 40% of patients with colorectal cancer. Conventionally, colorectal cancer with wild-type KRAS gene is effectively treated by administration of an anti-EGFR antibody, such as cetuximab, that suppresses signal transduction from EGFR. This treatment has been a great success. However, the anti-EGFR antibody is known as being ineffective against KRAS-gene-mutant colorectal cancer (Non-patent Documents 1 and 2, for example). A reason for this ineffectiveness in KRAS-gene-mutant colorectal cancer is probably the following: RAS mutation causes a lack of GTPase; RAS is constitutively active; signals downstream of RAS are turned on at all times; proliferation, survival, invasion, and anti-apoptotic activity of the cell are further induced; and, as a result, the action of the anti-EGFR antibody is canceled.
According to reports, blocking the signals downstream of RAS has an antitumor effect on KRAS-gene-mutant colorectal cancer cells. For example, Patent Document 3 reports that a MEK1/2 inhibitor can suppress proliferation of KRAS-gene-mutant colorectal cancer cells. Patent Document 4 reports that the suppressive effect of a MEK1/2 inhibitor on proliferation of KRAS-gene-mutant colorectal cancer cells is enhanced when the MEK1/2 inhibitor is used in combination with cetuximab.
A microRNA is a small RNA molecule of 18 to 24 nucleotides and is found in a wide range of eukaryotes. About 1,000 human miRNAs have been found. The miRNA is a short, single-stranded, endogenously-expressed RNA molecule first reported in 1993. From DNA, an RNA molecule having a loop structure is transcribed, which is called pri-miRNA. The loop is cleaved by an enzyme to yield a pre-miRNA. The pre-miRNA is exported from the nucleus. Then, from the pre-miRNA, a miRNA sequence of 20 to 25 bases is cut out by Dicer. The miRNA sequence is taken in by an RNA-induced silencing complex (RISC), which is a complex of ribonucleic acid and protein Argonaute. As a result, a miRNA-RISC complex is formed, which binds to the 3′UTR of mRNA and suppresses gene expression. The pairing between a miRNA molecule and an mRNA molecule is not perfect, and therefore a single miRNA molecule can have more than one target genes. This means that a single miRNA molecule can be regulated by targeting a plurality of genes, which is an important feature of miRNA.
The expression pattern of microRNA in KRAS-gene-mutant colorectal cancer has not yet been identified. Therefore, if analysis on changes in microRNAs in KRAS-gene-mutant colorectal cancer caused by activation of signal transduction pathways induced by KRAS-gene mutation can successfully establish a treatment that corrects aberration of the microRNAs, patients with KRAS-gene-mutant colorectal cancer can be helped.